Abstract
Imiquimod, an immunomodulator with no direct in vitro antiviral activity, has in vivo anti-herpesvirus activity by inducing interferon and enhancing other only partially defined immune responses. Imiquimod treatment of primary genital herpes simplex virus (HSV) infection in guinea pigs reduces the level of genital disease by 90%. We further investigated its utility as suppressive therapy of recurrent disease in animals that had recently recovered from primary genital HSV-2 disease. Imiquimod administered intravaginally once per day for 5 days reduced the number of recurrences only during treatment, while a 21-day regimen reduced the number of recurrences for 8 weeks. For the entire 10 weeks of observation, overall numbers of recurrences were reduced 67% by the 21-day imiquimod treatment (P < 0.0001). Latent HSV in ganglia was not affected by either regimen. Increased circulating alpha interferon activity was observed during therapy with both regimens. Interferon levels rapidly returned to baseline with cessation of treatment. Posttreatment, 5-day imiquimod treatment did not provide clinical benefit or enhancement of cell-mediated or cytokine responses. Twenty-one-day imiquimod treatment reduced both the number of clinical recurrences and levels of HSV antibody for 5 to 6 weeks posttreatment compared with the placebo. Additionally, 21-day imiquimod treatment enhanced HSV antigen-specific interleukin 2 production and proliferative responses by mononuclear cells (P < 0.001) for 4 weeks after treatment. Twenty-one-day imiquimod therapy suppressed recurrent HSV genital disease during and for weeks after therapy, enhanced memory-dependent cytokine and T-cell responses, and reduced the level of antibody responses.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bernstein D. I., Harrison C. J. Effects of the immunomodulating agent R837 on acute and latent herpes simplex virus type 2 infections. Antimicrob Agents Chemother. 1989 Sep;33(9):1511–1515. doi: 10.1128/aac.33.9.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bernstein D. I., Lovett M. A., Bryson Y. J. The effects of acyclovir on antibody response to herpes simplex virus in primary genital herpetic infections. J Infect Dis. 1984 Jul;150(1):7–13. doi: 10.1093/infdis/150.1.7. [DOI] [PubMed] [Google Scholar]
- Bernstein D. I., Miller R. L., Harrison C. J. Adjuvant effects of imiquimod on a herpes simplex virus type 2 glycoprotein vaccine in guinea pigs. J Infect Dis. 1993 Mar;167(3):731–735. doi: 10.1093/infdis/167.3.731. [DOI] [PubMed] [Google Scholar]
- Bernstein D. I., Stanberry L. R., Harrison C. J., Kappes J. C., Myers M. G. Antibody response, recurrence patterns and subsequent herpes simplex virus type 2 (HSV-2) re-infection following initial HSV-2 infection of guinea-pigs: effects of acyclovir. J Gen Virol. 1986 Aug;67(Pt 8):1601–1612. doi: 10.1099/0022-1317-67-8-1601. [DOI] [PubMed] [Google Scholar]
- Bernstein D. I., Stanberry L. R., Harrison C. J., Shukla R., Kappes J. C., Myers M. G. Antibody response to herpes simplex virus glycoprotein D: effects of acyclovir and relation to recurrence. J Infect Dis. 1987 Sep;156(3):423–429. doi: 10.1093/infdis/156.3.423. [DOI] [PubMed] [Google Scholar]
- Crumpacker C. S., Schnipper L. E., Marlowe S. I., Kowalsky P. N., Hershey B. J., Levin M. J. Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. N Engl J Med. 1982 Feb 11;306(6):343–346. doi: 10.1056/NEJM198202113060606. [DOI] [PubMed] [Google Scholar]
- Finkelman F. D., Svetic A., Gresser I., Snapper C., Holmes J., Trotta P. P., Katona I. M., Gause W. C. Regulation by interferon alpha of immunoglobulin isotype selection and lymphokine production in mice. J Exp Med. 1991 Nov 1;174(5):1179–1188. doi: 10.1084/jem.174.5.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harrison C. J., Jenski L., Voychehovski T., Bernstein D. I. Modification of immunological responses and clinical disease during topical R-837 treatment of genital HSV-2 infection. Antiviral Res. 1988 Dec 1;10(4-5):209–223. doi: 10.1016/0166-3542(88)90032-0. [DOI] [PubMed] [Google Scholar]
- Harrison C. J., Myers M. G. Peripheral blood mononuclear cell-mediated cytolytic activity during cytomegalovirus (CMV) infection of guinea pigs. J Med Virol. 1988 Aug;25(4):441–453. doi: 10.1002/jmv.1890250408. [DOI] [PubMed] [Google Scholar]
- McLaren C., Chen M. S., Ghazzouli I., Saral R., Burns W. H. Drug resistance patterns of herpes simplex virus isolates from patients treated with acyclovir. Antimicrob Agents Chemother. 1985 Dec;28(6):740–744. doi: 10.1128/aac.28.6.740. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mertz G. J., Eron L., Kaufman R., Goldberg L., Raab B., Conant M., Mills J., Kurtz T., Davis L. G. Prolonged continuous versus intermittent oral acyclovir treatment in normal adults with frequently recurring genital herpes simplex virus infection. Am J Med. 1988 Aug 29;85(2A):14–19. [PubMed] [Google Scholar]
- Stanberry L. R., Harrison C. J., Bernstein D. I., Burke R. L., Shukla R., Ott G., Myers M. G. Herpes simplex virus glycoprotein immunotherapy of recurrent genital herpes: factors influencing efficacy. Antiviral Res. 1989 May-Jun;11(4):203–214. doi: 10.1016/0166-3542(89)90005-3. [DOI] [PubMed] [Google Scholar]
- Straus S. E., Takiff H. E., Seidlin M., Bachrach S., Lininger L., DiGiovanna J. J., Western K. A., Smith H. A., Lehrman S. N., Creagh-Kirk T. Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir. N Engl J Med. 1984 Jun 14;310(24):1545–1550. doi: 10.1056/NEJM198406143102401. [DOI] [PubMed] [Google Scholar]
- Weinberg A., Basham T. Y., Merigan T. C. Regulation of guinea-pig immune functions by interleukin 2: critical role of natural killer activity in acute HSV-2 genital infection. J Immunol. 1986 Nov 15;137(10):3310–3317. [PubMed] [Google Scholar]